Crosslinking of the B cell antigen receptor surface immunoglobulin (Ig) induces activation of the Src-family and Syk tyrosine protein kinases and subsequent tyrosine phosphorylation of Shc., PtdIns-3 kinase and PLC gamma 2. In contrast, co-crosslinking surface Ig with the B cell IgG Fc receptor (Fc gamma R) prevents B cell proliferation and differentiation in a process termed "negative signaling." Co-crosslinking these receptors can arise by several mechanisms during a normal immune response in which secreted Ig blocks further generation of secretory antibody, thereby acting as a negative feedback system. Defects of negative feedback can lead to autoantibody formation and contribute to autoimmune pathologies by allowing continued and inappropriate Ig secretion. Furthermore, rheumatoid factor, an IgM anti-IgG Fc antibody, can block negative signaling by interfering with the binding secreted Ig with the Fc gamma R. The precise nature of the inhibitory signal(s) derived from Fc receptors promoting negative feedback and blocking B cell activation are not known. Preliminary studies of negative signaling in this laboratory demonstrated that activation of upstream kinases, Src-family and p72syk, are unaffected by co-crosslinking sIg and Fc gamma R. In contrast, we observed a selective block in the tyrosine phosphorylation and activation of PLC gamma 2 and activation-induced protein interactions of Shc. Inhibition of both events may, at least in part, be mediated by tyrosine phosphorylation and Shc-association of p145ship, a novel inositol 5'-phosphatase, and/or by activation of the phosphotyrosine phosphatase PTPIC. Experiments are proposed here to better understand the mechanism(s) of signaling events associated with negative feedback brought on by sIg-Fc gamma R co-crosslinking. Such information may reveal novel therapeutic targets in autoimmune pathology and contribute to the etiology of such diseases.